State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China.
Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, P. R. China.
Cancer Commun (Lond). 2023 Jul;43(7):808-833. doi: 10.1002/cac2.12428. Epub 2023 Jun 28.
Clear cell renal cell carcinoma (ccRCC) is the most lethal renal cancer. An overwhelming increase of patients experience tumor progression and unfavorable prognosis. However, the molecular events underlying ccRCC tumorigenesis and metastasis remain unclear. Therefore, uncovering the underlying mechanisms will pave the way for developing novel therapeutic targets for ccRCC. In this study, we sought to investigate the role of mitofusin-2 (MFN2) in supressing ccRCC tumorigenesis and metastasis.
The expression pattern and clinical significance of MFN2 in ccRCC were analyzed by using the Cancer Genome Atlas datasets and samples from our independent ccRCC cohort. Both in vitro and in vivo experiments, including cell proliferation, xenograft mouse models and transgenic mouse model, were used to determine the role of MFN2 in regulating the malignant behaviors of ccRCC. RNA-sequencing, mass spectrum analysis, co-immunoprecipitation, bio-layer interferometry and immunofluorescence were employed to elucidate the molecular mechanisms for the tumor-supressing role of MFN2.
we reported a tumor-suppressing pathway in ccRCC, characterized by mitochondria-dependent inactivation of epidermal growth factor receptor (EGFR) signaling. This process was mediated by the outer mitochondrial membrane (OMM) protein MFN2. MFN2 was down-regulated in ccRCC and associated with favorable prognosis of ccRCC patients. in vivo and in vitro assays demonstrated that MFN2 inhibited ccRCC tumor growth and metastasis by suppressing the EGFR signaling pathway. In a kidney-specific knockout mouse model, loss of MFN2 led to EGFR pathway activation and malignant lesions in kidney. Mechanistically, MFN2 preferably binded small GTPase Rab21 in its GTP-loading form, which was colocalized with endocytosed EGFR in ccRCC cells. Through this EGFR-Rab21-MFN2 interaction, endocytosed EGFR was docked to mitochondria and subsequently dephosphorylated by the OMM-residing tyrosine-protein phosphatase receptor type J (PTPRJ).
Our findings uncover an important non-canonical mitochondria-dependent pathway regulating EGFR signaling by the Rab21-MFN2-PTPRJ axis, which contributes to the development of novel therapeutic strategies for ccRCC.
透明细胞肾细胞癌（ccRCC）是最致命的肾癌。大量患者经历肿瘤进展和预后不良。然而，ccRCC 肿瘤发生和转移的分子事件仍不清楚。因此，揭示潜在机制将为 ccRCC 开发新的治疗靶点铺平道路。在这项研究中，我们试图研究线粒体融合蛋白 2（MFN2）在抑制 ccRCC 肿瘤发生和转移中的作用。
使用癌症基因组图谱数据集和我们独立的 ccRCC 队列中的样本分析 MFN2 在 ccRCC 中的表达模式和临床意义。体外和体内实验，包括细胞增殖、异种移植小鼠模型和转基因小鼠模型，用于确定 MFN2 在调节 ccRCC 恶性行为中的作用。RNA 测序、质谱分析、共免疫沉淀、生物层干涉测量和免疫荧光用于阐明 MFN2 抑制肿瘤作用的分子机制。
我们报道了 ccRCC 中的一种肿瘤抑制途径，其特征是线粒体依赖性表皮生长因子受体（EGFR）信号失活。这个过程是由外膜蛋白 MFN2 介导的。MFN2 在 ccRCC 中下调，与 ccRCC 患者的良好预后相关。体内和体外实验表明，MFN2 通过抑制 EGFR 信号通路抑制 ccRCC 肿瘤生长和转移。在肾脏特异性敲除小鼠模型中，MFN2 的缺失导致 EGFR 通路激活和肾脏中的恶性病变。在机制上，MFN2 优先与小 GTPase Rab21 结合，以其 GTP 加载形式存在，该形式与 ccRCC 细胞中内吞的 EGFR 共定位。通过这种 EGFR-Rab21-MFN2 相互作用，内吞的 EGFR 被停靠到线粒体上，随后被驻留在 OMM 上的酪氨酸蛋白磷酸酶受体型 J（PTPRJ）去磷酸化。
我们的发现揭示了一种重要的非经典线粒体依赖性途径，通过 Rab21-MFN2-PTPRJ 轴调节 EGFR 信号，为 ccRCC 的新型治疗策略的发展做出了贡献。
